EP0066124B1 - Pyridothienopyridazinverbindungen - Google Patents

Pyridothienopyridazinverbindungen Download PDF

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Publication number
EP0066124B1
EP0066124B1 EP82104051A EP82104051A EP0066124B1 EP 0066124 B1 EP0066124 B1 EP 0066124B1 EP 82104051 A EP82104051 A EP 82104051A EP 82104051 A EP82104051 A EP 82104051A EP 0066124 B1 EP0066124 B1 EP 0066124B1
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Prior art keywords
compound
formula
carboxy
alkyl
hydroxy
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP82104051A
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English (en)
French (fr)
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EP0066124A1 (de
Inventor
Raymons D. Youssefyeh
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USV Pharmaceutical Corp
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USV Pharmaceutical Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D495/04—Ortho-condensed systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D495/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms
    • C07D495/12—Heterocyclic compounds containing in the condensed system at least one hetero ring having sulfur atoms as the only ring hetero atoms in which the condensed system contains three hetero rings
    • C07D495/14—Ortho-condensed systems

Definitions

  • the invention relates to new chemical compounds possessing valuable pharmaceutical activity. It particularly relates to pyridothienopyridazines possessing useful anti-allergy activity and having the structure wherein m
  • alkyl groups in alkyl per se and in hydroxyalkyl alkoxy, mercaptoalkyl, alkylmercapto, aminoalkyl, alkylamino, alkanoyl, carbalkoxy, aralkyl, alkylsulfinyl and alkylsulfonyl are either straight-chain or branched lower alkyl groups containing from 1 to 6 carbon atoms.
  • the acyl group of the aforesaid acyloxy groups is any organic acid radical from which the radical OH has been removed from the acid group.
  • the corresponding radicals of the following acids are preferred: acetic, benzoic, isobutyric, pentanoic, cyclohexanecarboxylic, toluic, toluenesulfonic, napthalenesulfonic, phenylacetic, methanesulfonic, and similar acids.
  • Hydrocarbylcarboxylic and sulfonic acids in which the hydrocarbyl group is alkyl, cycloalkyl, aryl and aralkyl, preferably containing up to a total of 10 carbon atoms are preferred.
  • the alkenyl and alkynyl groups may be straight-chain or branched and contain from 2 to 6 carbon atoms.
  • the aryl groups contain froma 6 to 10 carbon atoms and include phenyl, a-naphthyl, and ⁇ -naphthyl. These groups may carry substituents such as alkyl, alkenyl, alkynyl, hydroxy, alkoxy, mercaptoalkyl, alkylmercapto, amino, alkylamino, cyano, carboxy, carbalkoxy, sulfinyl, sulfonyl, trifluoromethyl, methylenedioxy, halogen, and nitro.
  • halogen substituents are preferably chlorine, bromine and trifluoromethyl.
  • the compounds of the present invention are capable of forming salts with acids and when acid groups such as carboxyl groups are present, salts with bases.
  • acid groups such as carboxyl groups are present
  • salts with bases Preferred are salts formed with pharmaceutically-acceptable acids and bases.
  • Suitable acid addition salts include salts of inorganic acids such as hydrochloric, sulfuric and phosphoric and organic acids such as acetic, lactic, benzoic, nicotinic, malic, succinic, tartaric, citric, mandelic and the like.
  • Suitable basic salts include salts of alkali and alkaline earth metals, iron, and amines.
  • the preferred compounds of the present invention are those wherein n is 1, R, is lower alkyl, R 2 is carboxy or carbalkoxy and R 3 is hydroxy or alkoxy.
  • the compounds of the present invention may be prepared by the following reaction:
  • R 2 is carbalkoxy.
  • the R 2 carbalkoxy group can be readily saponified to a free carboxylic acid and, if desired, the carboxyl group removed, . e.g., by heating or by replacement reactions.
  • Compounds of structure II can be prepared by reaction of a compound of the formula: with a compound of the formula: especially where R 2 is carbalkoxy, with the formation of hydrogen halide as a by-product.
  • Compounds of structure I can also be prepared by ring closure of a compound of the formula: with hydrazine; or by diazotization and ring closure of a compound of the formula: or by ring-closure of compounds of the formulae: by elimination of HX and aromatization of the dihydropyridine ring.
  • peroxides or peracids such as hydrogen peroxide, isobutylperoxide, benzoylperoxide, peracetic acid and perbenzoic acid which are exemplary but not exhaustic of the reagents to be used for the oxidation.
  • peroxides or peracids such as hydrogen peroxide, isobutylperoxide, benzoylperoxide, peracetic acid and perbenzoic acid which are exemplary but not exhaustic of the reagents to be used for the oxidation.
  • the reaction conditions may lead to formation of N-oxides, especially with pyr
  • the 4-OH group can be modified as by etherification with hydrocarbyl groups by reaction with hydrocarbyl halides by removal of hydrogen halide or equivalent derivatives such as dihydrocarbyl sulfates and the like.
  • the 4-OH group can be acylated with organic acids to form corresponding esters such as acetates, benzoates, sulfonates, phosphates, malonates, citrates and the like.
  • the 4-OH can be replaced by a variety of substituents, e.g., halide, or simply removed as by catalytic hydrogenolysis or other known reactions such as chemical reduction.
  • substituents can be introduced into the products produced by the hereindescribed synthetic procedures by the usual substitution reactions such as alkylation, nitration, acylation, and the like or by conversion of existing substituents such as nitro to amino by reduction and amino to halo by diazotization and replacement of the diazo group with halo and equivalent groups.
  • the aforesaid reactions can be conveniently carried out in organic solvents at temperatures ranging from 0° to the reflux temperature of the reaction mixture.
  • the reaction periods are determined by the temperature selected for the reaction and the nature of the reactants.
  • Progress of the reactions can be determined by removal of aliquots from the reaction mixture and analysis for either the reactants, the products, or both to determine the relative concentrations thereof.
  • reaction mixtures are digested by heating for extended periods usually at the reflux temperature of the reaction mixture.
  • the solvent selected for the foregoing reactions is water-miscible in which case solvents such as dioxane, ethanol, methanol, acetone, dimethylformamide, diethylacetamide, and tetrahydrofuran are used. Water immiscible solvents can also be used.
  • the reactions are preferably accomplished in the presence of a hydrogen halide acceptor such as inorganic bases, e.g., sodium hydroxide, sodium carbonate and lime, or organic bases such as amines, e.g., trimethylamine, aniline, pyridine and the like.
  • a hydrogen halide acceptor such as inorganic bases, e.g., sodium hydroxide, sodium carbonate and lime, or organic bases such as amines, e.g., trimethylamine, aniline, pyridine and the like.
  • the diazotization reactions called for in the foregoing are accomplished by known procedures employing, for example, sodium nitrite or equivalent nitrite such as isoamynitrite in the presence of an acid such as acetic acid or a mineral acid such as hydrochloric or sulfuric acid. These reactions are usually conducted at about room temperature and even lower, e.g., to about 0°C.
  • Aromatization can be accomplished by known methods by reacting with reagents to remove hydrogen from the substrate compound.
  • the substrate can be heated with suifur or other such reagent, e.g., 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, to prepare the fully aromatized product, particularly, the aromatized pyrido ring.
  • the compounds of the present invention show strong activity as inhibitors of wheal formation in the passive cutaneous anaphylaxis (PCA) screen and as inhibitors of histamine release from passively sensitized rat mast cells (RMC), making them useful in the treatment of allergy.
  • the compounds exhibit ED 50 values of from 1.0 to 50.0 mg/kg on oral administration in the PCA screen and I 50 values of from 1 to 100 ⁇ m in the RMC screen.
  • the compounds may be administered orally or parenterally in the treatment of allergies and related conditions, and it will be within the skill of the practitioner to determine the exact amount to be administered and the mode of administration.

Claims (27)

1. Verbindung der allgemeinen Formel
Figure imgb0015
worin bedeuten:
R, Alkyl, Alkenyl, Alkinyl, Halogen, Nitro, Cyano, Carboxy, Carboxyalkyl, Carbalkoxy, Alkanoyl, Trihalogenmethyl, Aryl, Aralkyl, Mercapto, Mercaptoalkyl, Alkylmercapto, Hydroxy, Hydroxyalkyl, Alkoxy, Acyloxy, Amino, Aminoalkyl, Alkylamino, Sulfinyl, Sulfonyl oder Methylendioxy,
m eine ganze Zahl von 0 bis einschließlich 2,
n eine ganze Zahl von 0 bis einschließlich 3, und
R2 und R3 unbabhängig voneinander Wasserstoff, Alkyl, Alkenyl, Alkinyl, Hydroxy, Hydroxyalkyl, Alkoxy, Acyloxy, Halogen, Amino, Aminoalkyl, Alkylamino, Alkanoylamino, Mercapto, Mercaptoalkyl, Alkylmercapto, Carboxy, Carbalkoxy, Alkysulfinyl, Alkylsulfonyl, Arylsulfinyl oder Arylsulfonyl, wobei die Alkyl-, Alkenyl- und Alkinylgruppen bis zu 6 Kohlenstoffatome und die Arylgruppen 6 bis 10 Kohlenstoffatome enthalten; und Salze dieser Verbindungen.
2. Verbindung der allgemeinen Formel
Figure imgb0016
worin bedeuten:
n eine ganze Zahl von 0 bis einschließlich 3,
R, Alkyl, Alkenyl, Alkinyl, Halogen, Nitro, Cyano, Carboxyl, Carboxyalkyl, Alkanoyl, Trihalogenmethyl, Aryl, Aralkyl, Mercapto, Mercaptoalkyl, Alkylmercapto, Hydroxy, Hydroxyalkyl, Alkoxy, Acyloxy, Amino, Aminoalkyl, Alkylamino, Sulfinyl oder Sulfonyl, und
R2 und R3 unabhängig voneinander Wasserstoff, Alkyl, Alkenyl, Alkinyl, Hydroxy, Hydroxyalkyl, Alkoxy, Acyloxy, Halogen, Amino, Aminoalkyl, Alkylamino, Alkanoylamino, Mercapto, Mercaptoalkyl, Alkylmercapto, Carboxy, Carbalkoxy, Alkylsulfinyl, Alkylsulfonyl, Arylsulfinyl oder Arylsulfonyl, wobei die Alkyl-, Alkenyl- und Alkinylgruppen bis zu 6 Kohlenstoffatome und die Arylgruppen 6 bis 10 Kohlenstoffatome enthalten; und Salze dieser Verbindungen.
3. Verbindung der allgemeinen Formel
Figure imgb0017
worin bedeuten:
R, Alkyl mit 1 bis 6 Kohlenstoffatomen,
R2 Wasserstoff, Carboxy oder Carbalkoxy;

und Salze dieser Verbindungen, insbesondere Säure-Additionssalze.
4. Verbindung nach einem der Ansprüche 1 bis 3, dadurch gekennzeichnet, daß R1 Methyl bedeutet.
5. Verbindung nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß R2 Wasserstoff bedeutet.
6. Verbindung nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß R2 Carboxy bedeutet.
7. Verbindung nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß R2 Carbalkoxy bedeutet.
8. Verbindung nach einem der Ansprüche 1 bis 4, dadurch gekennzeichnet, daß R2 Carbethoxy bedeutet.
9. 3-Carboxy-4-hydroxy-7-methyl-pyrido[3',2':4,5]thieno[3,2―C]pyridazin.
10. Säure-Additionssalz der Verbindung gemäß Anspruch 9.
11. Verfahren zur Herstellung von Verbindungen der allgemeinen Formel (I), umfassend
a) die Diazotierung einer Verbindung der nachstehenden Formel (II)
Figure imgb0018
b) die Ringschlußbildung einer Verbindung der nachstehenden Formel (V) mit hydrazin
Figure imgb0019
c) die Diazotierung und Ringschlußbildung einer Verbindung der nachstehenden Formel (VI)
Figure imgb0020
oder
d) die Ringschlußbildung einer Verbindung der nachstehenden Formel (VII) oder (VIII) durch Eliminieren von Halogenwasserstoff und Aromatisierung des resultierenden Produkts
Figure imgb0021
worin
R1, R2, R3, n und m wie in Anspruch 1 definiert sind und X Halogen bedeutet, sowie wahlweise Anbringen von Substituenten an den so hergestellten Verbindungen durch Substitutions- oder Umwandlungsreaktionen;

und wahlweise Bilden von Salzen dieser Verbindungen mit Säuren und Basen, vorzugsweise pharmazeutisch annehmbare Säure-Additionssalze.
12. Verfahren nach Anspruch 11, dadurch gekennzeichnet, daß das Produkt eine Verbindung der Formel (I) ist, worin m = 0.
13. Verfahren nach Anspruch 11, dadurch gekennzeichnet, daß das Produkt eine Verbindung der Formel (I) ist, worin bedeuten:
n = 1,
m = 0 bis 2,
R1 Alkyl,
R2 Wasserstoff, Carboxy oder Carbalkoxy und
R3 = OH.
14. Verfahren nach Anspruch 11, dadurch gekennzeichnet, daß das Produkt eine Verbindung der Formel (I) ist, worin bedeuten:
n = 1,
m = 0 bis 2,
R, Methyl,
R2 Wasserstoff, Carboxy oder Carbalkoxy und
R3 = OH.
15. Verfahren nach einem der Ansprüche 11 bis 14, dadurch gekennzeichnet, daß das Produkt eine Verbindung der Formel (I) ist, worin bedeuten:
n = 1,
m = 0 bis 2,
R1 Alkyl und
R2 Carbonyl.
16. Verfahren nach einem der Ansprüche 11 bis 14, dadurch gekennzeichnet, daß das Produkt eine Verbindung der Formel (I) ist, worin bedeuten:
n = 1,
m = 0 bis 2,
R, Alkyl und
R2 Carbalkoxy.
17. Verfahren nach einem der Ansprüche 11 bis 14, dadurch gekennzeichnet, daß Produkt eine Verbindung der Formel (I) ist, worin bedeuten:
n = 1,
m = 0 bis 2,
R1 Alkyl und
R2 Carbethoxy.
18. Verfahren nach einem der Ansprüche 11 bis 14, dadurch gekennzeichnet, daß das Produkt eine Verbindung der Formel (I) ist, worin bedeuten:
n = 1, ―
m = 0 bis 2,
R, Alkyl und
R2 Wasserstoff.
19. Verfahren nach Anspruch 11, dadurch gekennzeichnet, daß das Produkt 3-Carboxy-4-hydroxy-7-methyl-pyrido[3',2':4,5]thieno[3,2-c]pyridazin ist.
20. Verfahren nach Anspruch 11, dadurch gekennzeichnet, daß das Produkt ein Säure-Additionssalz von 3-Carboxy-4-hydroxy-7-methyl-pyrido[3',2':4,5]thieno[3,2-c]pyridazin ist.
21. Verbindungen gemäß den Ansprüchen 1 bis 10 zur Verwendung in der Behandlung von Allergien und verwandten Zuständen.
EP82104051A 1981-05-18 1982-05-10 Pyridothienopyridazinverbindungen Expired EP0066124B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US06/264,756 US4355164A (en) 1981-05-18 1981-05-18 Pyridothienopyridazine anti-allergy compounds
US264756 1981-05-18

Publications (2)

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EP0066124A1 EP0066124A1 (de) 1982-12-08
EP0066124B1 true EP0066124B1 (de) 1984-09-19

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Country Status (12)

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US (1) US4355164A (de)
EP (1) EP0066124B1 (de)
JP (1) JPS57193481A (de)
AU (1) AU559728B2 (de)
CA (1) CA1202306A (de)
DE (1) DE3260771D1 (de)
DK (1) DK221682A (de)
ES (4) ES512194A0 (de)
IE (1) IE52890B1 (de)
NZ (1) NZ200628A (de)
PH (1) PH18463A (de)
ZA (1) ZA823355B (de)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4602019A (en) * 1983-04-22 1986-07-22 Warner-Lambert Company Indeno[1,2-c]pyridazin-3-one derivatives useful as cardiotonic and antihypertensive agents
US4734431A (en) * 1987-01-27 1988-03-29 Merrell Dow Pharmaceuticals Inc. Thiopyranodipyrazoles and their use as bronchodilators
JP6840931B2 (ja) * 2015-03-09 2021-03-10 東ソー株式会社 縮環芳香族化合物の製造方法

Also Published As

Publication number Publication date
IE821195L (en) 1982-11-18
JPS57193481A (en) 1982-11-27
ES521596A0 (es) 1984-07-01
ES8501404A1 (es) 1984-12-01
CA1202306A (en) 1986-03-25
DE3260771D1 (en) 1984-10-25
ES521597A0 (es) 1984-12-01
US4355164A (en) 1982-10-19
PH18463A (en) 1985-07-18
ES8307807A1 (es) 1983-09-01
ES521598A0 (es) 1984-12-01
ES8501403A1 (es) 1984-12-01
ZA823355B (en) 1983-03-30
EP0066124A1 (de) 1982-12-08
AU8365782A (en) 1982-11-25
AU559728B2 (en) 1987-03-19
NZ200628A (en) 1986-04-11
IE52890B1 (en) 1988-03-30
DK221682A (da) 1982-11-19
ES8405804A1 (es) 1984-07-01
ES512194A0 (es) 1983-09-01

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